The beta-amyloid protein, also referred to as A-4 and beta-protein, is a major constituent of the amyloid deposits in neuritic plaques and cerebrovascular walls in the brains of patients with Alzheimer's disease (AD). The size of deposited protein is between 4-5 kDa, although the recent isolation of cDNAs encoding it reveals that this is just a fragment of a much larger precursor, composed of 695 amino acids. A-4 occupies positions 597-638 of the APP sequence. The post-translational events that generate it from APP are unknown, and the specific biochemical events leading to its accumulation at cellular and tissue levels remain to be elucidated. Abnormalities in the posttranslational events that lead to protein modification and eventually to amyloid fibril deposition could arise at many stages: in the glycosylation of the nascent protein, in modifications such as phosphorylation and sulfation, or in the proteolytic processing of the 695 amino acid precursor. Preliminary studies were undertaken by us on the biosynthesis and processing of AD associated APP in cultured normal human fibroblasts and human neuroblastoma cells by immunochemical methods. The work demonstrates for the first time the existence of two post-translational forms of the protein: a secreted, high molecular weight sulfated form and an intracellular, lower molecular weigh tyrosine phosphorylated form. Processing appears to proceed differently for the two forms. The intracellular protein appears to undergo amino-terminal processing, giving rise to smaller fragments whereas the sulfated form does not undergo any further processing after it is released from the cell surface. Further studies on the proteolytic processing of cellular APP in normal and AD fibroblasts and normal and AD brain, on the normal post-translational modifications of both cellular and secreted APP, and on the endocytosis and degradation of the membrane-associated secreted APP are proposed.